Remarkably, in the field of neuroscience the male-to-female ratio of single-sex studies was 5. The authors examined how the investigator preference for studying male animals originated, and they discuss the adverse consequences of this male sex bias in preclinical research for human health. This article is an excellent resource for gaining an understanding of the historic existence of a sex bias in preclinical animal and human research across ten major biological disciplines including Animal Behavior, Behavioral Physiology, Endocrinology, General Biology, Immunology, Neuroscience, Pharmacology, Physiology, Reproduction, and Zoology.
One of the reasons preclinical research has historically been predominantly conducted on male animals is the mistaken assumption that female mammals are intrinsically more variable than males because of the estrous cycle. This assumption of greater female trait variability was called into question by Mogil and Chanda, who conducted a meta-analysis of nociceptive responses in forty strains of inbred mice and concluded that there were no sex differences in the response variability [ 7 ].
The authors found that for any endpoint studied, variability was not greater in females than males and in fact for several traits, the variability was greater in males. The authors identify three classes of sex differences. Included in type I differences are endpoints that are present in one sex but not the other.
For example, only females get pregnant or, for behaviors, courtship rituals, and copulatory behavior differs between males and females. This paper is also a resource for how to study the cause of sex differences and includes decision tree strategies and the methodology for addressing these strategies. For example, the first recommended experiment is to determine if a sex difference is due to gonadal hormones since most reported sex differences are due to adult gonadal hormone levels.
To address this question, the outcome parameter is compared between adult males and females in the intact and gonadectomized state. Then, depending upon the findings, gonadal hormone replacement studies may be indicated. While this article focuses on the brain, the concepts are relevant to many disciplines. The authors organized this paper as a series of decision tree questions and then provided highly detailed methodologies on how to study the role of male and female gonadal hormones using endocrine ablation and hormone replacement therapy in animals and how to differentiate developmental from adult origin gonadal hormone effects.
In addition, the authors discuss animal models that can be used to investigate the role of the sex chromosomes independently of the gonadal hormones and vice versa.
This paper also discusses how to gain insight into the cause of sex differences in humans by taking advantage of naturally occurring changes in the endocrine state across the male and female life span. Missing from this review, however, is the value of using naturally occurring endocrine disorders e. Another excellent resource for investigators interested in how to design and conduct investigations into the cause of sex differences using cells and tissues from animals or whole animal physiology was written by Miller et.
This article highlights the need to consider reproductive status e. In addition, Miller et al. This paper is also an excellent reference for understanding the impact of how the accumulation of small sex differences can have major effects on outcomes. Methodological approaches to being able to recognize small sex differences by reducing experimental variation, sufficiently powering studies, and by conducting meta-analyses are presented. In addition, this article provides a valuable resource for considering overlooked variables in designing sex difference research including sex differences in the pharmacokinetics and pharmacodynamics of drug action when conducting a pharmacological intervention.
This is an excellent resource for Animal Care and Use Committees during their review of animal protocols as Holdcroft recommends guidelines for encouraging disclosure of information that affects sex or gender differences such as strain variations and age of animals. Moreover, she provides the rationale for why preclinical research design should consider the impact of sex on disease incidence and outcomes.
Investigators are cautioned that the possibility exists for misleading results for improperly conducted SGA, which could mistakenly influence medical management. This small book is accessible to those with even basic understanding of biology and outlines designs for SGBA within basic science and preclinical studies, clinical and healthcare systems research, and social and cultural determinants.
Missing within its context are references concerning biomedical device, biomarker, and diagnostic test developments, which are important components of SGBA approaches. The tool itself is easy to use and consists of six series of questions that include Background, Criteria for considering studies, Methods, Results and Analysis, Discussion and Conclusion, and Table of Included Studies. The tool is a seven-step plan that reviews the main sex and gender issues to consider in each stage of research including 1 Relevance Check, 2 Literature Search, 3 Formulation of research questions and hypotheses, 4 Research methods and sample, 5 Data analysis and interpretation, 6 Reporting, and 7 Conclusions and recommendations.
This resource is valuable for a broad range of scientists and offers an easy to use checklist designed to assist the integration of sex and gender aspects in biomedical ad health research methodologies. It provides an earlier version of the seven questions described above; however, it has limited utility as an actual tool and serves more in the capacity to promote and create awareness for consideration of sex and gender in research design.
This tool has not been externally validated but is systematic, detailed, and should be useful to assess appropriate application of SGBA to the evidence synthesized by systematic reviews across disciplines. These are invaluable resources to assist researchers in identifying sex-based research questions for future areas of study in particular medical specialties. National Research Council with recommendations for studying sex differences in medicine, translational research, drug development, and reporting these differences in research publications [ 21 ].
This broader viewpoint enables this resource to be a valuable template for workshops addressing sex differences in many disciplines. This symposium covers examples of sex differences in outcome and diagnostics using traumatic brain injury and cardiovascular research as examples, which serves as a useful motivator for researchers to explore sex differences in clinical medicine. There is also a focus on statistical design of studies assessing the impact of sex and gender. Additionally, two books were identified as clinical research resources.
Included in the book is a history of the science of sex differences, a description of the scientific method, and particular chapters on what were current issues at the time, including math, spatial ability, women and masochism, males and aggression, mother-blame, women and hormones, verbal ability, and dependence of females.
However, surprisingly, it is still relevant. This resource is helpful to researchers to understand US and international drug regulation and marketing as well as clinical drug development.
Cases of both underinclusion and overinclusion of women in clinical drug development programs are presented and associated efficacy and safety concerns are discussed. Ratios were calculated according to the proportion of women in the disease population. Presentation of the ratio for new drugs by disease and for biologics by disease is presented for multiple diseases.
This analysis can assess the adequacy of representation by female subjects in clinical trials. Included is a table with a helpful list of questions to ask about study design and analysis when thinking about sex and gender issues in clinical research. This well-organized article could provide a path to investigate gender differences in pharmacokinetics for a new drug, but it should be noted that pregnant women and women on hormonal therapies were excluded from this review.
This case puts forward the idea that sex differences can be overemphasized to the exclusion of other factors, such as height and weight.
Thus, sex differences can be emphasized for reasons having more to do with medical marketing than optimal patient care. It begins by defining sex and gender and underscores the importance of sex and gender research. The review thoroughly discusses ethical barriers to public health studies. It answers as well as discusses questions on gender biases, ethics, and methodologies, and the establishment of guidelines and offers recommendations for improving gender representation and evaluation on ethics committees and in public health research methodology including that data are disaggregated by sex and by socioeconomic factors.
This resource provides background on the origins of sex- and gender-based analysis and the major concepts of sex, gender, diversity, and equity as well as how these concepts relate to health. It also provides guidance on how to conduct sex- and gender-based analysis. This piece stresses the importance of assessing the impact of other variables e. It introduces the concept that more complex analyses are key to moving beyond simple assessments of differences between women and men toward an understanding of why these differences exist and how best to respond to them.
Finally, this resource treats sex- and gender-based analysis as a process, rather than a tool or template, thereby emphasizing its flexibility and transferability across sectors, disciplines, and regions.
This article describes the limitations of what is known regarding the role of gender in occupational lung disease. The authors focus attention on the challenges faced by researchers when investigating the impact of gender in occupational health and disease, which includes sex and gender differences in tasks, work shifts, effectiveness of protective practices and measures, lung mechanics, co-morbidities, and pre-existing conditions as well as the limitations in record keeping by sex.
This resource serves as an example of the methodological challenges that face researchers when investigating the influence of sex and gender in occupational-associated diseases including differences in perception, and the interaction of environmental, sociocultural, and biologic factors.
What are the Connections-and Why Does it Matter? The resource can be used as a guide in integrating gender mainstreaming at every stage of research.
This article educates scientific researchers in the complexity and multiple ways the factors of sex and gender can independently and synergistically affect health outcomes. The case examples presented in the paper highlight that gender relations influence expression—and interpretation—of biological traits, and also that sex-linked biological characteristics can, in some cases, contribute to or amplify gender differentials in health.
Gender and sex matter! The author breaks down suggestions to apply to each step of the research process, from developing research questions and study design to conducting the study, analyzing and interpreting findings, to publication of findings.
This resource will be most useful to researchers, scientific journal editors, and grant funders. It highlights the importance of classifying gender theoretical concepts as central and interlinked in health sciences through definitions of sex, gender, intersectionality, embodiment, gender equity, and gender equality.
This particular essay discusses ten difficulties in the treatment of gender in sex research, reflects on their origins, and reviews the theory behind it. This resource may be useful to researchers as a basic platform for gender-based studies. The purpose of this primer is to explore the following question: The primer includes the following: Previous research in this area used pooled data from both genders; where in actuality men and women have and use their household assets differently.
This toolkit provides definitions, statistical methods, and case studies designed to assist the researcher in collecting appropriate gender data.
This online toolkit is organized in three sections. The first section provides an overview of the key concepts in gender and asset ownership. The second section describes measures for assessing the impact of gender on asset data collection including the tools, best practices, and approaches as well as the limitations of these methods.
The final section summarizes the best practices and provides key recommendations for gender asset collection. An appendix offers additional resources, case studies, and a guide for integrating gender into household surveys.
The second is to develop a model to summarize characteristics that can differentiate sex and gender blind research, sex and gender differences research, and gender research. The goal is to encourage researchers to become aware of shortcomings in traditional gender-blind research and the developmental potentials in gender research. The limitation of this model is that the complexities of the connections between sex and gender are not fully taken into account.
Conclusions It is critically important to consider both sex and gender in research design, implementation, analysis, and interpretation. Sex- and gender-based comparisons can provide clues into disease mechanisms that could lead to new drug targets and treatment strategies, while analyzing data by sex and gender will enhance scientific rigor and reproducibility.
Not considering sex and gender has adverse consequences for human health, not only through missed opportunities for therapeutic discovery but because sex and gender can impact the frequency and magnitude of adverse events. NIH has recognized the importance of these issues and, soon, failure to take sex into account will make applicants noncompliant when applying for NIH funding. Including sex as a biological variable into research design can be a new and potentially complicated process for both established researchers that now need to change the way in which they have been conducting research and for new researchers seeking guidance in developing appropriate approaches.
This timely review provides a state-of-the-art annotated bibliography of sex and gender analytic resources to encourage and assist researchers in their efforts to design studies that include sex and gender, and to collect, analyze, and report sex and gender disaggregated data. Additionally, the authors sought to perform a review of each resource identified using previously established qualities. To our knowledge, such a comprehensive review has not previously been conducted.
Our review of the literature through yielded 69 resources. After excluding resources that did not meet the eligibility criteria, 38 resources were identified and a database of these resources was created. Of the seven questions the review team set out to answer, we were not able to answer two questions. This lack of data could potentially represent a lack of rigorous study design for the resources and may indicate limitations in their future impact and reproducibility.
In addition, this highlights the continued need to improve available resource tools for researchers that meet rigorous standards and measured outcomes. Taking both sex and gender into account in research are necessary, although not sufficient, to create evidence-based prevention, screening, diagnosis, and treatment plans for individuals and populations.
Since the completion of this study, several resources have become newly available to assist researchers.